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      FXTAS is difficult to differentiate from neuronal intranuclear inclusion disease through skin biopsy: a case report

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          Abstract

          Background

          Both fragile X-associated tremor/ataxia syndrome (FXTAS) and late-onset neuronal intranuclear inclusion disease (NIID) show CGG/GGC trinucleotide repeat expansions. Differentiating these diseases are difficult because of the similarity in their clinical and radiological features. It is unclear that skin biopsy can distinguish NIID from FXTAS. We performed a skin biopsy in an FXTAS case with cognitive dysfunction and peripheral neuropathy without tremor, which was initially suspected to be NIID.

          Case presentation

          The patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C ( NOTCH2NLC) gene . We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 ( FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID.

          Conclusions

          For the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis, is essential. Further investigations in additional cases based on genetic analysis are needed to elucidate the clinical and pathological differences between FXTAS and NIID.

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          Most cited references9

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          Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

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            Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease

            Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
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              Clinicopathological features of adult-onset neuronal intranuclear inclusion disease

              Neuronal intranuclear inclusion disease (NIID) has highly variable clinical manifestations. Sone et al. describe the clinical and pathological features of 57 adult-onset cases diagnosed by postmortem dissection/antemortem skin biopsy. They report ‘dementia dominant’ and ‘limb weakness’ subtypes, and recommend consideration of NIID in the differential diagnosis of leukoencephalopathy and neuropathy.
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                Author and article information

                Contributors
                ohshita4@hiroshima-u.ac.jp
                Journal
                BMC Neurol
                BMC Neurol
                BMC Neurology
                BioMed Central (London )
                1471-2377
                12 October 2021
                12 October 2021
                2021
                : 21
                : 396
                Affiliations
                [1 ]GRID grid.414157.2, ISNI 0000 0004 0377 7325, Department of Neurology, , Hiroshima City Asa Citizens Hospital, ; 2-1-1, Kabeminami, Asakita-ku, Hiroshima, 731-0293 Japan
                [2 ]GRID grid.257022.0, ISNI 0000 0000 8711 3200, Department of Clinical Neuroscience and Therapeutics, , Hiroshima University Graduate School of Biomedical and Health Sciences, ; 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Japan
                [3 ]GRID grid.440118.8, ISNI 0000 0004 0569 3483, Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Caner Center, ; 3-1 Aoyama-cho, Kure, Hiroshima, 737-0023 Japan
                [4 ]GRID grid.257022.0, ISNI 0000 0000 8711 3200, Department of Epidemiology, , Research Institute for Radiation Biology and Medicine, Hiroshima University, ; 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Japan
                [5 ]GRID grid.258331.e, ISNI 0000 0000 8662 309X, Department of Supportive and Promotive Medicine of the Municipal Hospital, Faculty of Medicine, , Kagawa University, ; 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 Japan
                [6 ]GRID grid.411234.1, ISNI 0000 0001 0727 1557, Aichi Medical University, ; Nagakute, Aichi Japan
                [7 ]GRID grid.411234.1, ISNI 0000 0001 0727 1557, Department of Neuropathology, , Institute for Medical Science of Aging, Aichi Medical University, ; Nagakute, Aichi 480-1195 Japan
                [8 ]Department of Neurology, National Hospital Organization Suzuka National Hospital, 3-2-1, Kasado, Suzuka, Mie 513-8501 Japan
                Author information
                http://orcid.org/0000-0002-3915-2963
                Article
                2425
                10.1186/s12883-021-02425-z
                8513318
                34641814
                7e6340a4-df7c-4e86-a7ed-4140ba6ba391
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 29 January 2021
                : 1 October 2021
                Funding
                Funded by: Funding Programme for Next Generation World-Leading Researchers of JSPS
                Award ID: LS088
                Award Recipient :
                Funded by: Grant-in-Aid for Scientific Research on Innovative Areas of MEXT
                Award ID: JP23111008
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007449, Takeda Science Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/501100012029, Tsuchiya Foundation;
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2021

                Neurology
                fxtas,niid,skin biopsy,genetic analysis
                Neurology
                fxtas, niid, skin biopsy, genetic analysis

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